Paraneoplastic ocular sarcoidosis in the setting of recurrent rectal carcinoid tumor diagnosed by F18-fluorodeoxyglucose PET CT.

PURPOSE: Nuclear medicine imaging can provide a noninvasive means of distinguishing inflammatory mass lesions from oncologic intraocular tumors. OBSERVATION: We report a case of paraneoplastic ocular sarcoidosis with choroidal mass lesions that was initially concerning for choroidal metastasis of a primary carcinoid tumor. PET CT was utilized with two different tracers to characterize the choroidal mass as being FDG-avid, consistent with a sarcoid-like lesion, and lacking the Gallium (Ga-68) DOTATAE uptake of carcinoid tumor metastases. CONCLUSIONS AND IMPORTANCE: Functional imaging is valuable to distinguish clinically similar inflammatory verses oncologic intraocular pathology.

The association of (18)F-FDG PET and glucose metabolism biomarkers GLUT1 and HK2 in p16 positive and negative head and neck squamous cell carcinomas.

OBJECTIVES: To investigate the relationship between FDG-PET maximum standard uptake value (SUVmax), p16, EGFR, GLUT1 and HK2 expression in head and neck squamous cell carcinomas (HNSCC). MATERIALS AND METHODS: Immunohistochemical staining of p16, EGFR, GLUT1 and HK2 was performed on primary tumor tissue from 97 locally advanced HNSCC patients treated with definitive chemoradiation. SUVmax along with p16, EGFR, GLUT1 and HK2 expression were analyzed for associations including local control, locoregional control and disease free survival. RESULTS: Pretreatment SUVmax in primary tumors did not differ when stratified by p16, EGFR or GLUT1 expression but SUVmax was significantly higher in HK2 expressing tumors (p=0.021) and in tumors with higher T-stage (p=0.022). GLUT1 expression was significantly higher in p16 negative (p<0.001) and EGFR positive tumors (p<0.01). HK2 expressing tumors were associated with EGFR positive tumors (p=0.022) but not with p16 or GLUT1 expression. EGFR positive, p16 negative and high GLUT1 expressing tumors were associated with worse local control and disease free survival on univariate analyses. After adjusting for patient and treatment characteristics p16 status was the only factor that predicted for outcome on multivariate analysis. CONCLUSIONS: High GLUT1 expression was associated with EGFR positive and p16 negative HNSCC tumors. GLUT1 maybe an important biomarker in HNSCC but its expression appears dependent on p16 status.

Detection of Aberrant Right Subclavian Artery by PET/CT.

An aberrant right subclavian artery can be diagnosed by PET/CT, as demonstrated in this case of a 70-y-old man undergoing PET/CT for staging of squamous cell carcinoma of the right lung. It is important to report this finding during the evaluation of oncologic patients, to prevent severe complications that may arise from various oncologic interventions.

Revisiting the Marrow Metabolic Changes after Chemotherapy in Lymphoma: A Step towards Personalized Care.

Purpose. The aims were to correlate individual marrow metabolic changes after chemotherapy with bone marrow biopsy (BMBx) for its potential value of personalized care in lymphoma. Methods. 26 patients (mean age, 58 ± 15 y; 13 female, 13 male) with follicular lymphoma or diffuse large B-cell lymphoma, referred to FDG-PET/CT imaging, who had BMBx from unilateral or bilateral iliac crest(s) before chemotherapy, were studied retrospectively. The maximal standardized uptake value (SUV) was measured from BMBx site over the same area on both initial staging and first available restaging FDG-PET/CT scan. Results. 35 BMBx sites in 26 patients were evaluated. 12 of 35 sites were BMBx positive with interval decrease in SUV in 11 of 12 sites (92%). The remaining 23 of 35 sites were BMBx negative with interval increase in SUV in 21 of 23 sites (91%). The correlation between SUV change over the BMBx site before and after chemotherapy and BMBx result was significant (P < 0.0001). Conclusions. This preliminary result demonstrates a strong correlation between marrow metabolic changes (as determined by FDG PET) after chemotherapy and bone marrow involvement proven by biopsy. This may provide a retrospective means of personalized management of marrow involvement in deciding whether to deliver more extended therapy or closer followup of lymphoma patients.

Granulomatous disease: is it a nuisance or an asset during PET/computed tomography evaluation of lung cancers?

OBJECTIVES: To evaluate combined PET-computed tomography (CT) criteria for differentiating between granulomatous disease (GD) and malignancy (CA) in oncologic PET-CT studies. METHODS: Sixty-two patients who were referred for fluoro-2-deoxyglucose (FDG) PET-CT evaluation of pulmonary lesion(s) without a history of concurrent infection were studied. PET-CT was performed 1.5 h after intravenous administration of 555 MBq 18F-FDG in the fasting state with oral contrast. Combined PET-CT criteria including (i) calcifications (Ca2+) within lymph nodes, (ii) Ca2+ in lung nodules, (iii) liver and/or spleen Ca2+, (iv) locations of lung lesion(s), (v) hilar FDG uptake, (vi) comparison of lung versus maximum mediastinal FDG uptake, (vii) lymph node uptake not in the most probable lymphatic drainage pathway from a particular lung lesion, and (viii) extra pulmonary abnormal FDG uptake were each assigned a numerical score (0-3) with progressively higher score and sum of scores toward the increasing likelihood of GD. These patients either had pathological confirmation by biopsy/resection or were followed radiographically for a period of 2 years (CA=13; GD=49). Discriminant analysis was performed on all the above criteria with this gold standard. Simple t-test and box plot analysis were also performed on the summation of the scores (from 0 in CA to 13 in GD). RESULTS: When all eight criteria were entered into discriminant analysis, the combined PET-CT criteria classified correctly 71% of patients with a sensitivity of 65% and specificity of 92% for GD. The most significant discriminating criterion was FDG uptake in the lung lesion(s) less than maximum mediastinal uptake (P=0.01). The sum scores in GD and CA were significantly different (4.9+/-2.4 vs. 3.2+/-1.5, respectively, P=0.014). Box plots showed a clear separation at a cut-off value of around 3.5. CONCLUSION: Results show that the set of combined PET-CT criteria are highly specific for GD, which is not necessarily a nuisance during oncologic evaluation. Knowledge of these criteria may attribute some of the abnormal PET findings to GD, which is a useful asset for quick recognition and clinical interpretation.

Assessment of progression and treatment response of optic pathway glioma with positron emission tomography using alpha-[(11)C]methyl-L-tryptophan.

PURPOSE: To report the utility of positron emission tomography (PET) with alpha-[(11)C]methyl-L-tryptophan (AMT) for monitoring progression and response to treatment of an isolated optic pathway glioma (OPG) in a 16-year-old girl. PROCEDURES: Positron emission tomography scanning of the brain was performed 20 minutes after intravenous administration of AMT. The AMT-PET images were reconstructed and examined for tumor uptake of the tracer in correlation with coregistered magnetic resonance images. RESULTS: The PET scan demonstrated increased uptake of AMT by OPG in a clinically symptomatic child whose magnetic resonance imaging (MRI) was inconclusive for morphological changes of the tumor. The tracer uptake was dramatically decreased on the images obtained after chemotherapy. Subsequently, AMT-PET revealed a new tumor lesion of increased AMT uptake when the patient developed vision problems and MRI showed no significant interval morphological changes. Significant vision improvement was observed after external beam radiotherapy for the newly identified tumor lesion. CONCLUSIONS: Positron emission tomography with alpha-[(11)C]methyl-L-tryptophan may be useful for monitoring progression and response to treatment of OPGs, which needs to be further investigated in a prospective study of more patients, including those with neurofibromatosis.

In vivo uptake and metabolism of alpha-[11C]methyl-L-tryptophan in human brain tumors.

Abnormal metabolism of tryptophan has been implicated in modulation of tumor cell proliferation and immunoresistance. alpha-[(11)C]Methyl-L-tryptophan (AMT) is a PET tracer to measure cerebral tryptophan metabolism in vivo. In the present study, we have measured tumor tryptophan uptake in 40 patients with primary brain tumors using AMT PET and standard uptake values (SUV). Tryptophan metabolism was further quantified in 23 patients using blood input data. Estimates of the volume of distribution (VD') and the metabolic rate constant (k(3)') were calculated and related to magnetic resonance imaging (MRI) and histology findings. All grade II to IV gliomas and glioneuronal tumors showed increased AMT SUV, including all recurrent/residual tumors. Gadolinium enhancement on MRI was associated with high VD' values, suggesting impaired blood-brain barrier, while k(3)' values were not related to contrast enhancement. Low-grade astrocytic gliomas showed increased tryptophan metabolism, as measured by k(3)'. In contrast, oligodendrogliomas showed high VD' values but lower k(3)' as compared with normal cortex. In astrocytic tumors, low grade was associated with high k(3)' and lower VD', while high-grade tumors showed the reverse pattern. The findings show high AMT uptake in primary and residual/recurrent gliomas and glioneuronal tumors. Increased AMT uptake can be due to increased metabolism of tryptophan and/or high volume of distribution, depending on tumor type and grade. High tryptophan metabolic rates in low-grade tumors may indicate activation of the kynurenine pathway, a mechanism regulating tumor cell growth. AMT PET might be a useful molecular imaging method to guide therapeutic approaches aimed at controlling tumor cell proliferation by acting on tryptophan metabolism.

Neuroprotection in experimental stroke with targeted neurotrophins.

More than 30 neurotrophins have been identified, and many of them have neuroprotective effects in brain ischemia or injury. However, all the clinical trials with several neurotrophins for the treatment of acute ischemic stroke or neurodegenerative diseases have failed so far, primarily because of their poor blood-brain barrier (BBB) permeability. This article is an overview of recent progress in the research focused on BBB targeted neurotrophins using a chimeric peptide approach, in which antitransferrin receptor antibody was used as a BBB delivery vector, and neurotrophin peptide was conjugated to the antibody via the avidin/biotin technology. Vasoactive intestinal peptide was the first model chimeric peptide to show an enhanced CNS effect after noninvasive peripheral administration. Brain-derived neurotrophic factor (BDNF) chimeric peptide was neuroprotective in rats subjected to transient forebrain ischemia, permanent focal ischemia, or transient focal ischemia. Delayed treatments with the BDNF chimeric peptide showed an effective time window of 1-2 h after ischemia. Basic FGF chimeric peptide was highly effective in the reduction of infarct volume in the rat model of permanent focal ischemia, with lowest effective dose of 1 mug per rat. Future studies in this exciting area include genetically engineered fusion proteins or humanized antibodies for BBB drug targeting with less immunogenicity and reduced working burden in the chemical conjugation, the use of antihuman insulin receptor antibody for higher BBB delivery efficiency, and combination therapies using chimeric neurotrophins plus other neuroprotectants to achieve additive or synergistic effects.

Imaging endogenous gene expression in brain cancer in vivo with 111In-peptide nucleic acid antisense radiopharmaceuticals and brain drug-targeting technology.

UNLABELLED: Imaging endogenous gene expression with sequence-specific antisense radiopharmaceuticals is possible if the antisense agent is enabled to traverse the biologic membrane barriers that separate the blood compartment from messenger RNA (mRNA) molecules in the cytoplasm of the target cell. The present studies were designed to image endogenous gene expression in brain cancer using peptide nucleic acid (PNA) antisense agents that were modified to allow for (a) chelation of the 111In radionuclide and (b) attachment to a brain targeting system, which delivers the PNA across both the blood-brain barrier (BBB) and the tumor cell membrane. METHODS: PNAs were designed that were antisense to either the rat glial fibrillary acidic protein (GFAP) mRNA or the rat caveolin-1alpha (CAV) mRNA. The PNA contained an amino-terminal diethylenetriaminepentaacetic acid moiety to chelate 111In and a carboxyl-terminal epsilon-biotinyl lysine residue, which enabled attachment to the delivery system. The latter comprised streptavidin (SA) and the murine OX26 monoclonal antibody to the rat transferrin receptor (TfR), which were joined by a thiol-ether linker. Control PNAs were not conjugated to SA-OX26. Brain tumors developed after the intracerebral injection of rat RG2 glial cells in adult Fischer CD344 rats. GFAP and CAV gene expression in the tumor in vivo was monitored by confocal microscopy and Northern blotting with GFAP and CAV complementary DNAs. RESULTS: If the PNA was not targeted to the TfR, then no imaging of any brain structures was possible, owing to the absence of PNA transport across the BBB. Conjugation of the 111In-GFAP-PNA to the SA-OX26 delivery system did not image brain cancer, owing to the downregulation of the GFAP mRNA in brain glial tumors. In contrast, brain cancer was selectively imaged with the 111In-CAV-PNA conjugated to SA-OX26 owing to upregulation of CAV gene expression in brain cancer. CONCLUSION: Imaging endogenous gene expression in vivo with PNA antisense radiopharmaceuticals is possible if drug-targeting technology is used. Attachment of the PNA antisense agent to the targeting ligand enables the antisense radiopharmaceutical to traverse biologic membrane barriers and access intracellular target mRNA molecules.

A novel computerized approach to enhancing lung tumor detection in whole-body PET images.

Positron emission tomography (PET) is complimentary to other imaging modalities such as CT and MRI and provides a unique and effective means for detecting tumors in vivo through tissue metabolism measurement. At the majority of clinics, only the attenuation-corrected images are read by the physician for tumor diagnosis; the unconnected images are not examined, losing critically important information for a small portion of patients. We have developed a novel image processing method capable of automatically detecting and ranking tumor candidates in the lungs using the whole-body PET images. The intended utility is to visually prompt tumor candidates, assisting the physician to achieve better diagnosis, especially when the candidates appear to be subtle. The technique takes advantage of different information contents in the emission, corrected and uncorrected images. It processes the images three-dimensionally and the processing consists of segmentation, multi-thresholding with volume criterion, and heuristics-based tumor candidate ranking. This method is fast in computation and display and thus is suitable for real-time applications using high-end PCs. Our preliminary retrospective study involving nine patients has yielded promising results.

Positron emission tomography in diagnosis and management of invasive breast cancer: current status and future perspectives.

[18F]fluorodeoxyglucose positron emission tomography (FDG-PET) is a metabolic imaging modality that has increasing applications in oncology, neurology, and cardiology. Among the oncology applications, breast cancer is one of the most extensively studied diseases. FDG-PET has been performed for diagnosis, staging, and restaging of invasive breast cancer and for monitoring responsiveness to therapies. At the present time, the results of FDG-PET in detection of primary breast cancer and axillary staging are mixed and inconclusive. However, results demonstrating the superiority of FDG-PET over anatomic imaging modalities in detection of distant metastasis, recurrence, and monitoring therapies are relatively well documented. These applications have been accepted by medical professionals and the public, as evidenced by a recent decision by the Centers for Medicare and Medicaid Services (formerly Health Care Financing Agency) to provide coverage for the procedure. Future trends in this exciting area include development of novel breast cancer-specific PET radiopharmaceuticals and use of dedicated breast PET technologies for scans of breast/axillary lesions. PET/computed tomography technology, which combines anatomic and molecular/biochemical information, is also rapidly proliferating and should help to further improve the management of patients with breast cancer. The role of FDG-PET in breast cancer is increasing and evolving, and this metabolic imaging modality, in conjunction with newer tracers and other anatomic imaging methods, should improve diagnosis and management of patients with breast cancer

Hypoxia and reoxygenation of brain microvascular smooth muscle cells in vitro: cellular responses and expression of cerebral amyloid angiopathy-associated proteins.

Hypoxia is known to cause complex cascades of physiological, biochemical, and morphological changes in the brain. Cerebral microvascular smooth muscle cell (MV-SMC) damage may occur following hypoxic conditions and lead to SMC dysfunction. However, little is known about the exact cellular and molecular responses of these cells to hypoxia. To partly address these questions, MV-SMC were isolated from human brain, cultured and placed in conditions of ambient hypoxia (H) and hypoxia followed by reoxygenation (H/R). Cell morphology, proliferation, and the expression of amyloid precursor protein (APP) and cystatin C peptide were investigated and compared (after induction of hypoxia) between cerebral MV- and human aortic SMC. Our results show that MV-SMC proliferation was inhibited after 48 h of hypoxia and H/R, whereas aortic SMC proliferation was stimulated after 48 h of hypoxia and H/R. Hypoxia and H/R induced an increase of intracellular APP and cystatin C expression in both types of SMC, though the effect of H and H/R on APP upregulation was quantitatively more robust in MV-SMC than aortic SMC. Patterns of hypoxia-induced APP upregulation in SMC differed significantly from those found in cultured neuronal cells (PC12, NT2). These results suggest that hypoxia and H/R-induced APP and cystatin C upregulation appear to occur independently of the inhibition of cerebral MV-SMC proliferation. Overexpression of APP and cystatin C in response to hypoxia may thus represent an initiating event in the pathogenesis of amyloid angiopathy, or mediate progression of this microvascular lesion.